1. Field of the Invention
The present invention relates to a semi-synthesis of taxane derivatives useful in the preparation of docetaxel, from pure or crude paclitaxel or related taxane starting material, in particular, the semi-synthesis of protected taxane derivatives in a one pot reaction and its conversion to docetaxel.
2. Description of the Related Art
The taxane family of terpenes has received much attention in the scientific and medical community because the members of this family have demonstrated broad spectrum anti-leukemic and tumor-inhibitory activity. Docetaxel (1, Taxotere), a semi-synthetic analog, and paclitaxel (2, Taxol), a complex diterpene isolated from the bark of the Pacific yew tree (Taxus brevifolia) are arguably the most outstanding cancer chemotherapeutic substances discovered in recent times. For example, paclitaxel has been found to have activity against different forms of leukemia and against solid tumors in the breast, ovary, brain, and lung in humans. While paclitaxel can be obtained from the yew tree or semi-synthetically, only the latter option is currently available for the formation of non-natural docetaxel. The partial synthesis of this important compound has generally been accomplished through esterification of a derivative of the (2R,3S)phenylisoserine side chain with a protected form of 10-deacetylbaccatin III, a comparatively abundant natural product also present in the yew tree.

As disclosed in U.S. Pat. No. 4,814,470, taxotere has been found to have very good anti-tumor activity and better bio-availability than paclitaxel. Taxotere is similar in structure to paclitaxel, having t-butoxycarbonyl instead of benzoyl on the amino group at the 3′ position, and a hydroxy group instead of the acetoxy group at the C-10 position.
Docetaxel and paclitaxel may be prepared semi-synthetically from 10-deacetylbaccatin III or baccatin III as set forth in U.S. Pat. Nos. 4,924,011 and 4,924,012, by the reaction of a β-lactam and a suitably protected 10-deacetylbaccatin III or baccatin III derivative as set forth in U.S. Pat. No. 5,175,315, by a method using an oxazoline compound as set forth in International Patent Kokai No. Hei 7-504444, by a method using thioester compound as set forth in International Patent Kokai No. Hei 10-505360 or by a method using cinnamic acid as set forth in Tetrahedron, Vol. 42, p. 4451,1986, etc. 10-deacetylbaccatin III (10-DAB, 3) and Baccatin III (4) can be separated from mixtures extracted from natural sources such as the needles, stems, bark or heartwood of numerous Taxus species and have the following structures.

Although much of the research towards the semi-synthesis of paclitaxel and taxotere has involved 10-deacetylbaccatin III as the starting material, other taxanes from the Taxus species, such as 9-dihydro-13-acetylbaccatin III (9-DHB, 5), present in the Canadian yew (Taxus Canadensis), cephalomannine (6), 10-deacetyl taxol (10-DAT, 7), 7-xylosyl taxol (8), 10-deacetyl-7-xylosyl taxol (9) and a number of 7-epi-taxanes have been collected and identified.

As disclosed in U.S. patent application Ser. No. 10/695,416, which application is assigned to the assignee of the present invention, docetaxel and paclitaxel may also be prepared semi-synthetically from 9-dihydro-13-acetylbaccatin III.
However, the above methods thus far developed involve subjects such as reaction under the conditions of extremely low temperatures, generation of diastereomers, use of asymmetry controlling agents, and the reaction under strongly alkaline conditions, which cause problems upon the industrialization thereof.
Accordingly, there remains a need for new and improved processes for the preparation of taxane derivatives and their conversion to docetaxel, and also for the preparation of such taxane intermediates from crude and partially purified mixtures comprising a plurality of taxanes. The present invention addresses these needs and provides further related advantages.